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Study Discloses New Component Of Cells' Built-In Suicide Program

Date:

April 23, 1999

Source:

Dana-Farber Cancer Institute

Summary:

Scientists at Dana-Farber Cancer Institute and Duke University Medical Center have uncovered a new portion of the circuitry that controls the natural death of cells - a malfunction of which may underlie diseases ranging from cancer to heart disease to autoimmune disorders.

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Boston -- Scientists at Dana-Farber Cancer Institute and Duke University Medical Center have uncovered a new portion of the circuitry that controls the natural death of cells - a malfunction of which may underlie diseases ranging from cancer to heart disease to autoimmune disorders.

The study, published in the April 23 issue of Science, not only opens a previously uncharted area of cell life to scientific study, but also identifies new targets for therapies that can return diseased cells to the normal path of mortality.

"This research elucidates how cells naturally commit suicide, or undergo `apoptosis,'" says Joan Mannick, M.D., of Dana-Farber, who co-authored the study with Jonathan Stamler, M.D., a Howard Hughes Medical Institute researcher at Duke. "We now know that in addition to the controls on apoptosis that have already been identified, there's another control system that works in unison with them."

The study focuses on a protein called caspase which is an essential component of cells' suicide machinery.

In the laboratory, chemical bundles of nitric oxide (NO) can be made to attach to, or become detached from, caspase. This coupling and decoupling can have a powerful effect on a protein's activity. When caspase proteins are bound to NO, they're essentially handcuffed from performing their normal function. When the NO is removed, cell death can proceed.

But whether such binding and unbinding occurs in living cells - and what it would mean if it does - has been unclear. In fact, only a few types of proteins have been found to be attached to NO in cells.

The current study involved human lymphocytes, white blood cells that help provide immune protection against disease. Such cells perform a variety of functions, but one thing they don't do is produce much NO.

Mannick and her colleagues extracted caspase from lymphocytes that were in a "resting" state - that is, not yet embarked on apoptosis. To their surprise, they found the protein had an NO group attached.

"The fact that we found NO attached to proteins even in cells that produce very little of it indicates that NO may help regulate protein function in a much broader range of cells than was previously appreciated," Mannick says.

The nature of its role became clear when researchers triggered the cells' apoptosis mechanism. The caspase proteins collected from the apoptotic cells had lost their NO.

"This is the first time that NO has been found to attach and detach from caspase in living cells," Mannick says. "It represents a new control mechanism for cell death and, potentially, a new mechanism for controlling other cell functions."

Researchers were able to detect the presence or absence of NO thanks to technology developed by Stamler and his colleagues at Duke. The Duke team has developed new techniques which make it possible to find minute amounts of NO within cells.

Previous work by the Stamler lab has shown that NO represents a key on-off switch for a variety of cell functions. "The new study confirms that apoptosis is one of them," Stamler says. Besides demonstrating that the control system for apoptosis has a previously unknown layer of complexity, the new study may offer new prospects for therapy.

"Defects in apoptosis contribute not only to cancer, in which cells are blocked from committing suicide, but also in conditions such as stroke and neurodegenerative diseases, in which cells die too readily," Stamler says. "Knowing more about the system that controls apoptosis provides new opportunities for therapies aimed at correcting the system when it goes awry."

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